Endoplasmic reticulum stress, pancreatic β-cell degeneration, and diabetes.

Overwhelming of protein folding in the endoplasmic reticulum (ER)--referred to as "ER stress"--activates a set of intracellular signaling pathways termed the unfolded protein response (UPR). Beneficial outputs of the UPR promote adaptation in cells experiencing manageably low levels of ER stress. However, if ER stress reaches critically high levels, the UPR uses destructive outputs to trigger programmed cell death. Genetic mutations in various UPR components cause inherited syndromes of diabetes mellitus in both rodents and humans, implicating the UPR in the proper functioning and survival of pancreatic islet β cells. Markers of chronically elevated ER stress, terminal UPR signaling, and apoptosis are evident in β cells in these rare disorders; these markers are similarly present in islets of human patients with common forms of diabetes. These findings promise to enhance our molecular understanding of human diabetes significantly and may lead to new and effective therapies.

[1]  C. Betsholtz,et al.  Islet amyloid polypeptide — a novel controversy in diabetes research , 1992, Diabetologia.

[2]  A. Letai,et al.  Control of mitochondrial apoptosis by the Bcl-2 family , 2009, Journal of Cell Science.

[3]  Junying Yuan,et al.  A Selective Inhibitor of eIF2α Dephosphorylation Protects Cells from ER Stress , 2005, Science.

[4]  Kiyoshi Inoue,et al.  ASK1 is essential for endoplasmic reticulum stress-induced neuronal cell death triggered by expanded polyglutamine repeats. , 2002, Genes & development.

[5]  T. Buchanan,et al.  Gestational diabetes mellitus. , 2005, The Journal of clinical investigation.

[6]  M. Schapira,et al.  Regulated translation initiation controls stress-induced gene expression in mammalian cells. , 2000, Molecular cell.

[7]  Hiderou Yoshida,et al.  ATF6 Activated by Proteolysis Binds in the Presence of NF-Y (CBF) Directly to the cis-Acting Element Responsible for the Mammalian Unfolded Protein Response , 2000, Molecular and Cellular Biology.

[8]  K. Mori,et al.  Mammalian transcription factor ATF6 is synthesized as a transmembrane protein and activated by proteolysis in response to endoplasmic reticulum stress. , 1999, Molecular biology of the cell.

[9]  M. Katze,et al.  Pancreatic (cid:1) -Cell Failure and Diabetes in Mice With a Deletion Mutation of the Endoplasmic Reticulum Molecular Chaperone Gene P58 IPK , 2022 .

[10]  D. Ron,et al.  Perk is essential for translational regulation and cell survival during the unfolded protein response. , 2000, Molecular cell.

[11]  D. Scheuner,et al.  The unfolded protein response: a pathway that links insulin demand with beta-cell failure and diabetes. , 2008, Endocrine reviews.

[12]  D. Ron,et al.  Oxidative protein folding by an endoplasmic reticulum-localized peroxiredoxin. , 2010, Molecular cell.

[13]  D. Scheuner,et al.  Control of mRNA translation preserves endoplasmic reticulum function in beta cells and maintains glucose homeostasis , 2005, Nature Medicine.

[14]  Xueying Gu,et al.  Menin Controls Growth of Pancreatic ß-Cells in Pregnant Mice and Promotes Gestational Diabetes Mellitus , 2007, Science.

[15]  C. Weston,et al.  The JNK signal transduction pathway. , 2007, Current opinion in genetics & development.

[16]  D. Ron,et al.  Protein translation and folding are coupled by an endoplasmic-reticulum-resident kinase , 1999, Nature.

[17]  S. Fowler,et al.  Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. , 2002 .

[18]  D. Steiner.  New Aspects of Proinsulin Physiology and Pathophysiology , 2000, Journal of pediatric endocrinology & metabolism : JPEM.

[19]  S. Korsmeyer,et al.  Proapoptotic BAX and BAK: A Requisite Gateway to Mitochondrial Dysfunction and Death , 2001, Science.

[20]  Randal J. Kaufman,et al.  Endoplasmic Reticulum Stress Activates Cleavage of CREBH to Induce a Systemic Inflammatory Response , 2006, Cell.

[21]  G. Grodsky,et al.  Excessive Insulin Response to Glucose in Obese Subjects as Measured by Immunochemical Assay , 1963, Diabetes.

[22]  S. Bonner-Weir,et al.  Five stages of evolving beta-cell dysfunction during progression to diabetes. , 2004, Diabetes.

[23]  A. Tardivel,et al.  ER stress activates the NLRP3 inflammasome via an UPR-independent pathway , 2012, Cell Death and Disease.

[24]  L. Glimcher,et al.  Endoplasmic Reticulum Stress Links Obesity, Insulin Action, and Type 2 Diabetes , 2004, Science.

[25]  Peter Walter,et al.  On the mechanism of sensing unfolded protein in the endoplasmic reticulum. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[26]  Hiderou Yoshida,et al.  Transcriptional induction of mammalian ER quality control proteins is mediated by single or combined action of ATF6alpha and XBP1. , 2007, Developmental cell.

[27]  T. Curran,et al.  Proto-oncogene CT10-regulated kinase (CRK) is a pro-apoptotic transducer of endoplasmic reticulum stress , 2011, Nature Cell Biology.

[28]  Jennifer Lippincott-Schwartz,et al.  Stable Binding of ATF6 to BiP in the Endoplasmic Reticulum Stress Response , 2005, Molecular and Cellular Biology.

[29]  M. Permutt,et al.  Mice conditionally lacking the Wolfram gene in pancreatic islet beta cells exhibit diabetes as a result of enhanced endoplasmic reticulum stress and apoptosis , 2005, Diabetologia.

[30]  J. Kench,et al.  Endoplasmic reticulum stress contributes to beta cell apoptosis in type 2 diabetes , 2007, Diabetologia.

[31]  F. R. Papa,et al.  IRE1α Kinase Activation Modes Control Alternate Endoribonuclease Outputs to Determine Divergent Cell Fates , 2009, Cell.

[32]  L. Orci,et al.  Quantitation of Endocrine Cell Content in the Pancreas of Nondiabetic and Diabetic Humans , 1982, Diabetes.

[33]  F. R. Papa,et al.  Signaling cell death from the endoplasmic reticulum stress response. , 2011, Current opinion in cell biology.

[34]  D. Faustman,et al.  Persistence of Prolonged C-peptide Production in Type 1 Diabetes as Measured With an Ultrasensitive C-peptide Assay , 2012, Diabetes Care.

[35]  P. Arvan,et al.  Proinsulin Disulfide Maturation and Misfolding in the Endoplasmic Reticulum* , 2005, Journal of Biological Chemistry.

[36]  D. Ron.  Proteotoxicity in the endoplasmic reticulum: lessons from the Akita diabetic mouse. , 2002, The Journal of clinical investigation.

[37]  K. Kohno.  How transmembrane proteins sense endoplasmic reticulum stress. , 2007, Antioxidants & redox signaling.

[38]  J. Sambrook,et al.  Protein folding in the cell , 1992, Nature.

[39]  L. Hendershot,et al.  The modification and assembly of proteins in the endoplasmic reticulum. , 1993, Current opinion in cell biology.

[40]  Daniel J Klionsky,et al.  Eating the endoplasmic reticulum: quality control by autophagy. , 2007, Trends in cell biology.

[41]  F. Urano,et al.  Coupling of stress in the ER to activation of JNK protein kinases by transmembrane protein kinase IRE1. , 2000, Science.

[42]  J. Weissman,et al.  Road to Ruin: Targeting Proteins for Degradation in the Endoplasmic Reticulum , 2011, Science.

[43]  D. Scheuner,et al.  Cytoprotection by pre‐emptive conditional phosphorylation of translation initiation factor 2 , 2004, The EMBO journal.

[44]  Masataka Mori,et al.  Targeted disruption of the Chop gene delays endoplasmic reticulum stress-mediated diabetes. , 2002, The Journal of clinical investigation.

[45]  F. R. Papa,et al.  A kinase inhibitor activates the IRE1alpha RNase to confer cytoprotection against ER stress. , 2008, Biochemical and biophysical research communications.

[46]  Sounak Gupta,et al.  PERK Regulates the Proliferation and Development of Insulin-Secreting Beta-Cell Tumors in the Endocrine Pancreas of Mice , 2009, PloS one.

[47]  P. Walter,et al.  Intracellular signaling by the unfolded protein response. , 2006, Annual review of cell and developmental biology.

[48]  C. Sevier,et al.  Formation and transfer of disulphide bonds in living cells , 2002, Nature Reviews Molecular Cell Biology.

[49]  Jonathan S Weissman,et al.  Decay of Endoplasmic Reticulum-Localized mRNAs During the Unfolded Protein Response , 2006, Science.

[50]  Anne Bertolotti,et al.  Dynamic interaction of BiP and ER stress transducers in the unfolded-protein response , 2000, Nature Cell Biology.

[51]  M. Miura,et al.  A transgenic mouse model for monitoring endoplasmic reticulum stress , 2004, Nature Medicine.

[52]  A. Hattersley,et al.  Insulin gene mutations as a cause of permanent neonatal diabetes , 2007, Proceedings of the National Academy of Sciences.

[53]  T. Ørntoft,et al.  Global profiling of genes modified by endoplasmic reticulum stress in pancreatic beta cells reveals the early degradation of insulin mRNAs , 2007, Diabetologia.

[54]  K. Mori,et al.  Role of Disulfide Bridges Formed in the Luminal Domain of ATF6 in Sensing Endoplasmic Reticulum Stress , 2006, Molecular and Cellular Biology.

[55]  F. R. Papa,et al.  The UPR and cell fate at a glance , 2010, Journal of Cell Science.

[56]  Christine E. Becker,et al.  Activation of the NLRP3 inflammasome by islet amyloid polypeptide provides a mechanism for enhanced IL-1β in type 2 diabetes , 2010, Nature Immunology.

[57]  R. Kaufman,et al.  Adaptation to ER Stress Is Mediated by Differential Stabilities of Pro-Survival and Pro-Apoptotic mRNAs and Proteins , 2006, PLoS biology.

[58]  S. Lenzen,et al.  Low antioxidant enzyme gene expression in pancreatic islets compared with various other mouse tissues. , 1996, Free radical biology & medicine.

[59]  Hiderou Yoshida,et al.  A time-dependent phase shift in the mammalian unfolded protein response. , 2003, Developmental cell.

[60]  Stevan R. Hubbard,et al.  IRE1 couples endoplasmic reticulum load to secretory capacity by processing the XBP-1 mRNA , 2002, Nature.

[61]  Masahiko Kuroda,et al.  Cloning of mammalian Ire1 reveals diversity in the ER stress responses , 1998, The EMBO journal.

[62]  Jae-Hyoung Cho,et al.  Selective β-Cell Loss and α-Cell Expansion in Patients with Type 2 Diabetes Mellitus in Korea , 2003 .

[63]  Tomomi Gotoh,et al.  ER Stress Triggers Apoptosis by Activating BH3-Only Protein Bim , 2007, Cell.

[64]  Mari Nishino,et al.  Caspase-2 Cleavage of BID Is a Critical Apoptotic Signal Downstream of Endoplasmic Reticulum Stress , 2008, Molecular and Cellular Biology.

[65]  A. Strasser,et al.  The BCL-2 protein family: opposing activities that mediate cell death , 2008, Nature Reviews Molecular Cell Biology.

[66]  K. Mori,et al.  XBP1 mRNA Is Induced by ATF6 and Spliced by IRE1 in Response to ER Stress to Produce a Highly Active Transcription Factor , 2001, Cell.

[67]  R. Kaufman,et al.  A stress response pathway from the endoplasmic reticulum to the nucleus requires a novel bifunctional protein kinase/endoribonuclease (Ire1p) in mammalian cells. , 1998, Genes & development.

[68]  Chao Zhang,et al.  Bypassing a Kinase Activity with an ATP-Competitive Drug , 2003, Science.

[69]  Zhaohui Xu,et al.  The crystal structure of human IRE1 luminal domain reveals a conserved dimerization interface required for activation of the unfolded protein response , 2006, Proceedings of the National Academy of Sciences.

[70]  G. Lathrop,et al.  EIF2AK3, encoding translation initiation factor 2-α kinase 3, is mutated in patients with Wolcott-Rallison syndrome , 2000, Nature Genetics.

[71]  R. Kaufman,et al.  Ligand-independent Dimerization Activates the Stress Response Kinases IRE1 and PERK in the Lumen of the Endoplasmic Reticulum* , 2000, The Journal of Biological Chemistry.

[72]  Heather T. McFarlane,et al.  Atomic structures of amyloid cross-β spines reveal varied steric zippers , 2007, Nature.

[73]  R. Rizza,et al.  High Expression Rates of Human Islet Amyloid Polypeptide Induce Endoplasmic Reticulum Stress–Mediated β-Cell Apoptosis, a Characteristic of Humans With Type 2 but Not Type 1 Diabetes , 2007, Diabetes.

[74]  Subramaniam Pennathur,et al.  Chop deletion reduces oxidative stress, improves beta cell function, and promotes cell survival in multiple mouse models of diabetes. , 2008, The Journal of clinical investigation.

[75]  Danhong Lu,et al.  A mutation in the insulin 2 gene induces diabetes with severe pancreatic beta-cell dysfunction in the Mody mouse. , 1999, The Journal of clinical investigation.

[76]  J. Martinou,et al.  The Bcl-2 protein family. , 2000, Experimental cell research.

[77]  R. Kaufman.  Orchestrating the unfolded protein response in health and disease. , 2002, The Journal of clinical investigation.

[78]  E. Yilmaz,et al.  Chemical Chaperones Reduce ER Stress and Restore Glucose Homeostasis in a Mouse Model of Type 2 Diabetes , 2006, Science.

[79]  J. Weissman,et al.  Oxidative protein folding in eukaryotes , 2004, The Journal of cell biology.

[80]  Y. Sasaguri,et al.  Overexpression of peroxiredoxin 4 protects against high-dose streptozotocin-induced diabetes by suppressing oxidative stress and cytokines in transgenic mice. , 2010, Antioxidants & redox signaling.

[81]  Chao Zhang,et al.  IRE1 Signaling Affects Cell Fate During the Unfolded Protein Response , 2007, Science.

[82]  Neal N. Iwakoshi,et al.  Plasma cell differentiation requires the transcription factor XBP-1 , 2001, Nature.

[83]  A. Trusina,et al.  Real-Time Redox Measurements during Endoplasmic Reticulum Stress Reveal Interlinked Protein Folding Functions , 2008, Cell.

[84]  T. Sommer,et al.  ERAD: the long road to destruction , 2005, Nature Cell Biology.

[85]  M. Vranic,et al.  Ubiquitinated-Protein Aggregates Form in Pancreatic β-Cells During Diabetes-Induced Oxidative Stress and Are Regulated by Autophagy , 2007, Diabetes.

[86]  Kathryn L. Lipson,et al.  The Role of IRE1α in the Degradation of Insulin mRNA in Pancreatic β-Cells , 2008, PloS one.

[87]  P. Halban,et al.  Dominant negative pathogenesis by mutant proinsulin in the Akita diabetic mouse. , 2003, Diabetes.

[88]  J. Brodsky,et al.  Evolving questions and paradigm shifts in endoplasmic‐reticulum‐associated degradation (ERAD) , 2003, BioEssays : news and reviews in molecular, cellular and developmental biology.

[89]  Kathryn L. Lipson,et al.  WFS1 Is a Novel Component of the Unfolded Protein Response and Maintains Homeostasis of the Endoplasmic Reticulum in Pancreatic β-Cells* , 2005, Journal of Biological Chemistry.

[90]  Peter Walter,et al.  Functional and Genomic Analyses Reveal an Essential Coordination between the Unfolded Protein Response and ER-Associated Degradation , 2000, Cell.

[91]  E McEwen,et al.  Translational control is required for the unfolded protein response and in vivo glucose homeostasis. , 2001, Molecular cell.

[92]  Peter Walter,et al.  Unfolded Proteins Are Ire1-Activating Ligands That Directly Induce the Unfolded Protein Response , 2011, Science.

[93]  Amy S. Lee,et al.  Endoplasmic Reticulum Stress-induced Apoptosis , 2006, Journal of Biological Chemistry.

[94]  M. Permutt,et al.  Wolfram syndrome 1 gene negatively regulates ER stress signaling in rodent and human cells. , 2010, The Journal of clinical investigation.

[95]  R. Kaufman,et al.  ATF6alpha optimizes long-term endoplasmic reticulum function to protect cells from chronic stress. , 2007, Developmental cell.

[96]  Chao Tang,et al.  Rationalizing translation attenuation in the network architecture of the unfolded protein response , 2008, Proceedings of the National Academy of Sciences.